Prognosis based classification and tumor biology of uterine sarcomas

• Uterine stromal sarcomas are a heterogenous group of tumors ranging from low-grade stromal sarcomas with a relatively good survival but high risk of recurrence, to undifferentiated uterine sarcomas with a far worse prognosis. Little is known about their biology, and prognostic markers are lacking. The treatment options are limited mainly to surgery. Chemotherapy and radiotherapy have little or no effect on survival. Recent success with immunotherapy has opened a promising research field with potential to gain new insights into the biology, prognosis and therapy of uterine stromal sarcomas. In paper I we examined the correlation of clinicopathological factors, biomarkers and YWHAE-FAM22 translocation with prognosis in undifferentiated uterine sarcomas. Twenty-six cases from the Karolinska University Hospital’s archive were included, out of which 22 of them had paraffin blocks for translocation status and immunohistochemical analysis of p53, p16, Ki67, Cyclin-D1, estrogen receptor, progesterone receptor and Anillin. Our findings show that the cases could be divided into two prognostic groups based on mitotic index; the high mitotic index group with a statistically significant worse prognosis than the group with low mitotic index. In paper II we wanted to validate the results from paper I in an independent cohort of cases. A total of 40 cases of undifferentiated uterine sarcomas were included from the Norwegian Radium Hospital, the Mayo Clinic and Skåne University Hospital. Mitotic index was recorded and the cases were divided into high and low mitotic index groups based on the cut-off from paper I. The analysis showed that one-third of the patients survived beyond five years. In the adjusted survival analysis, mitotic index group and tumor stage were prognostic factors. In paper III we identified molecular subgroups of undifferentiated uterine sarcomas and evaluated the possible correlation with different clinicopathological parameters. The cohort of paper III consisted of 50 cases with undifferentiated uterine sarcomas from six different institutions. All cases had formalin-fixed paraffin-embedded tumor material used for isolation of DNA and RNA. In total 50 cases were analyzed for gene expression, copy number variation, cell morphometry and protein expression. Four groups with different mRNA expression pattern were identified. Gene ontology analysis showed an activation of pathways related to genital tract development, extracellular matrix, muscle function and proliferation in the different groups. The result of the chromosomal copy number analysis showed a spectrum of variation, from cases that were diploid or near diploid to cases with extensive chromosomal aberrations. The adjusted Cox Proportional Hazard model showed that the mitotic index group, the hormone receptor expression and the mRNA group had a statistically significant impact on overall survival. In the ontology analysis, the mRNA group with the worst prognosis showed overexpressed pathways related to the extracellular matrix (ECM). When further analyzed by image analysis the ECM group was characterized by reduced cell density and increased nuclear size compared to the other groups. The ECM group also showed higher expression of the four ECM related proteins matrix metalloproteinase 14, collagen 1, collagen 6 and fibronectin, when evaluated with immunohistochemistry. In paper IV we analyzed the prognostic significance of different immune markers in lowgrade endometrial stromal sarcomas (LGESS). The cohort consisted of 21 cases identified by searching the pathological database at the Karolinska University hospital and the Stockholm region cancer registry. All cases had formalin-fixed paraffin-embedded tumor material and follow-up data. Tissue microarrays consisting of two biopsies of tumor material from each case were constructed. Multiplex fluorescent immunohistochemistry in combination with digital image analysis in QuPath was used to quantitatively assess the expression of different immune markers, including CD8, FOXP3, CD68, CD163, IDO1, B7-H4 and PD-L1. A low ratio of CD8+/FOXP3+ cells was significantly associated with a favorable prognosis in LGESS. For patients with a high quantity of CD8+ T cells and B7- H4, a trend towards better survival was seen. The expression of B7-H4 is also a potential therapeutic target.

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